Association between Body Composition and the Risk of Portopulmonary Hypertension Assessed by Computed Tomography in Patients with Liver Cirrhosis

The aim of this study is to investigate the impact of body composition on the risk of portopulmonary hypertension using computed tomography (CT) in patients with liver cirrhosis. We retrospectively included 148 patients with cirrhosis treated at our hospital between March 2012 and December 2020. POPH high-risk was defined as main pulmonary artery diameter (mPA-D) ≥ 29 mm or mPA-D to ascending aorta diameter ratio ≥ 1.0, based on chest CT. Body composition was assessed using CT images of the third lumbar vertebra. The factors associated with POPH high-risk were evaluated using logistic regression and decision tree analyses, respectively. Among the 148 patients, 50% were females, and 31% were found to be high-risk cases on evaluation of chest CT images. Patients with a body mass index (BMI) of ≥25 mg/m2 had a significantly higher prevalence of POPH high-risk than those with a BMI < 25 mg/m2 (47% vs. 25%, p = 0.019). After adjusting for confounding factors, BMI (odds ratio [OR], 1.21; 95% confidence interval [CI], 1.10–1.33), subcutaneous adipose tissue index (OR, 1.02; 95% CI, 1.01–1.03), and visceral adipose tissue index (OR, 1.03; 95% CI, 1.01–1.04) were associated with POPH high-risk, respectively. In the decision tree analysis, the strongest classifier of POPH high-risk was BMI, followed by the skeletal muscle index. Body composition may affect the risk of POPH based on chest CT assessment in patients with cirrhosis. Since the present study lacked data on right heart catheterization, further studies are required to confirm the results of our study.


Introduction
Pulmonary hypertension (PH) is characterized by increased mean pulmonary artery pressure and can complicate the majority of cardiovascular and pulmonary disorders [1]. PH associated with portal hypertension is referred to as portopulmonary hypertension (POPH) and usually affects approximately 5% of patients with portal hypertension [1,2]. The precise pathogenesis of POPH is unclear; however, the major etiology of POPH is attributed to pulmonary vasoconstriction, which leads to increased mean pulmonary artery pressure and pulmonary vascular resistance [3]. Since POPH can cause right heart failure, the one and five-year survival rates of the patients without treatment are reported to be approximately 40% and 14%, respectively [4,5]. Therefore, the development of appropriate diagnostic and therapeutic strategies for POPH in the treatment of patients with cirrhosis is indispensable.

Study Design
This is a retrospective study including 148 Japanese cirrhosis patients who were admitted to the gastroenterology ward of Gifu University Hospital (Gifu, Japan) between March 2012 and December 2020. These patients were followed up until the last visit, death, or 24 March 2022, whichever occurred first. An opt-out method was used to obtain informed consent from all the patients due to the retrospective nature of this study. The Institutional Review Board of the Gifu University Graduate School of Medicine approved the study protocol (approval number: 2022-061). This study was conducted in accordance with the 2013 Declaration of Helsinki.
The inclusion criteria were patients with liver cirrhosis of any etiology who were aged ≥20 years and had undergone a CT examination. The exclusion criteria included a history of liver transplantation; active malignancies, including hepatocellular carcinoma; and comorbidities that may induce PH, cardiovascular disease, heart failure, lung disease, connective tissue disease, sarcoidosis, and thyroid disease. The diagnosis of liver cirrhosis was based on clinical, biochemical, and radiological features. The clinical characteristics and laboratory variables, including Child-Pugh score, a model for end-stage liver disease (MELD), and albumin-bilirubin (ALBI) scores, were assessed at the time of admission [13][14][15]. The risk of POPH, body composition, ascites, and portosystemic shunt was assessed using CT within 3 months of admission.

Assessment of POPH Risk Using Chest CT
The assessment of POPH risk using CT was based on the guidelines of the European Society of Cardiology and European Respiratory Society and a previous report [1,11]. The widest mPA-D, widest aAO-D, and inferior vena cava (IVC) were measured using CT, and the ratios of mPA-D and aAO-D (mPA-D/aAO-D) were calculated. Patients with mPA-D dilatation (≥29 mm) or increased mPA-D/aAO-D (≥1.0) were defined as 'POPH high-risk', whereas the other patients were defined as 'POPH low-risk' [11].

Assessment of Body Composition and Sarcopenia
Body composition was analyzed using CT images of the third lumbar vertebra and CT image analysis software (Synapse Vincent; Fujifilm, Tokyo, Japan). The skeletal muscle index (SMI), subcutaneous adipose tissue index (SATI), visceral adipose tissue index (VATI), and total adipose tissue index (TATI) were calculated from the skeletal muscle mass, subcutaneous adipose tissue, visceral adipose tissue, and total adipose tissue area at the third lumbar vertebra, respectively ( Figure 1) [16][17][18]. Patients with both reduced SMI (<42 cm 2 /m 2 in males and <38 cm 2 /m 2 in females) and handgrip strength (<28 kg in males and <18 kg in females) were diagnosed with sarcopenia based on the criteria proposed by the Japan Society of Hepatology [19,20]. Patients with body mass index (BMI) ≥ 25 mg/m 2 were diagnosed as obese.  15]. The risk of POPH, body composition, ascites, and portosystemic shunt was assessed using CT within 3 months of admission.

Assessment of POPH Risk Using Chest CT
The assessment of POPH risk using CT was based on the guidelines of the European Society of Cardiology and European Respiratory Society and a previous report [1,11]. The widest mPA-D, widest aAO-D, and inferior vena cava (IVC) were measured using CT, and the ratios of mPA-D and aAO-D (mPA-D/aAO-D) were calculated. Patients with mPA-D dilatation (≥29 mm) or increased mPA-D/aAO-D (≥1.0) were defined as 'POPH high-risk', whereas the other patients were defined as 'POPH low-risk' [11].

Assessment of Body Composition and Sarcopenia
Body composition was analyzed using CT images of the third lumbar vertebra and CT image analysis software (Synapse Vincent; Fujifilm, Tokyo, Japan). The skeletal muscle index (SMI), subcutaneous adipose tissue index (SATI), visceral adipose tissue index (VATI), and total adipose tissue index (TATI) were calculated from the skeletal muscle mass, subcutaneous adipose tissue, visceral adipose tissue, and total adipose tissue area at the third lumbar vertebra, respectively ( Figure 1) [16][17][18]. Patients with both reduced SMI (<42 cm 2 /m 2 in males and <38 cm 2 /m 2 in females) and handgrip strength (<28 kg in males and <18 kg in females) were diagnosed with sarcopenia based on the criteria proposed by the Japan Society of Hepatology [19,20]. Patients with body mass index (BMI) ≥ 25 mg/m 2 were diagnosed as obese. Figure 1. Assessment of skeletal muscle mass, subcutaneous adipose tissue, and visceral adipose tissue in patients with cirrhosis. The green, blue, and red areas represent SMI, SATI, and VATI in a female patient with cirrhosis (A,B) with and (C,D) without obesity. Abbreviations: BMI, body mass index; SATI, subcutaneous adipose tissue index; SMI, skeletal muscle index; VATI, visceral adipose tissue index.

Statistical Analyses
Baseline characteristics were expressed as medians and interquartile ranges for quantitative variables and as frequency and percentages for qualitative variables. Quantitative

Statistical Analyses
Baseline characteristics were expressed as medians and interquartile ranges for quantitative variables and as frequency and percentages for qualitative variables. Quantitative and qualitative variables were compared using the Mann-Whitney U and chi-square tests, respectively. The ability to identify POPH high-risk was evaluated using receiver operating characteristic (ROC) curve analysis, and the results were presented as the area under the ROC curve (AUC). The optimal cutoff values were assessed using the Youden index. Factors associated with POPH high-risk were analyzed using logistic regression analysis, and the results were expressed as odds ratios (ORs) with 95% confidence intervals (CIs). A decisiontree analysis was carried out to reveal the classifier associated with POPH high-risk. The Cox proportional hazards regression model was used for evaluating survival, and the results were expressed as hazard ratios (HRs) with 95% CIs. Survival curves were estimated using the Kaplan-Meier method, and the survival was compared using the log-rank test. Two-sided tests with a p-value < 0.05 were considered statistically significant. Statistical analyses were performed using JMP Pro version 16.2.0 (SAS Institute Inc., Cary, NC, USA) and R version 4.1.3 software (The R Foundation for Statistical Computing, Vienna, Austria).

Comparison of Cirrhotic Patients with Low-Risk and High-Risk for POPH Based on Chest CT
A comparison of the characteristics of patients with POPH low-and high-risk assessed using chest CT is shown in Table 1. Regarding the POPH risk assessment, the prevalence of patients with mPA-D dilatation and increased mPA-D/aAo-D was 29% (n = 43) and 7% (n = 11), respectively, and 31% of patients (n = 46) had at least one of these. Most POPH high-risk patients were females with higher BMI, higher prevalence of portosystemic shunt, dilated IVC, and lower MELD scores than low-risk patients. Regarding body composition, POPH high-risk patients had significantly higher SATI, VATI, and TATI values than low-risk patients, whereas there was no significant difference in SMI and sarcopenia between these groups.

Comparison of the Characteristics of Cirrhotic Patients with and without Obesity
Since higher BMI and increased levels of adipose tissue were found to be associated with POPH high-risk (Table 1), the next study examined the impact of obesity on patient background, including risk factors for POPH. As listed in Table 2, patients with obesity were more females and had a higher prevalence of hypertension and portosystemic shunt but a lower prevalence of ascites than those without obesity. In addition, SMI, SATI, VATI, and TATI were significantly higher in patients with obesity than in those without obesity. Regarding chest CT findings, the mPA-D (29 vs. 27 mm, p = 0.011) and IVC (29 vs. 27 mm, p = 0.019) were significantly dilated in obese patients than those without obesity. Consequently, the prevalence of POPH high-risk was significantly higher in obese patients than in non-obese patients (47% vs. 25%, p = 0.009; Figure 2).

Decision Tree Analysis for Factors Associated with POPH High-Risk
Next, decision tree analysis was performed to examine the factors preferentially associated with POPH high-risk. Based on the analysis, BMI was selected as the most important classifier to identify patients with high POPH risk. Patients with a BMI ≥ 32 kg/m 2 had the highest prevalence of POPH high-risk (90%), whereas patients with a BMI < 24 kg/m 2 had the lowest prevalence (17%). Among the patients with BMI ≥ 24 kg/m 2 and less than 32 kg/m 2 , SMI ≥ 39 cm 2 /m 2 was identified as an important classifier for POPH highrisk ( Figure 4).

Decision Tree Analysis for Factors Associated with POPH High-Risk
Next, decision tree analysis was performed to examine the factors preferentially associated with POPH high-risk. Based on the analysis, BMI was selected as the most important classifier to identify patients with high POPH risk. Patients with a BMI ≥ 32 kg/m 2 had the highest prevalence of POPH high-risk (90%), whereas patients with a BMI < 24 kg/m 2 had the lowest prevalence (17%). Among the patients with BMI ≥ 24 kg/m 2 and less than 32 kg/m 2 , SMI ≥ 39 cm 2 /m 2 was identified as an important classifier for POPH high-risk ( Figure 4).

Association between Body Composition and Survival in Patients with Cirrhosis
The Cox proportional hazards regression model was used to evaluate the association between body composition and survival in patients with cirrhosis (Table S3). The analyses revealed that although SATI (HR, 0.98; 95% CI, 0.96-0.99; p = 0.004) was associated with survival in patients with cirrhosis, no such association was found for SMI and VATI.

Discussion
Since the mortality of candidates for LT with POPH is extremely high, there have been many studies on POPH among this population [7]. In addition, recent studies have attempted to explore POPH in patients with more preserved liver functional reserves [9,10]. For early diagnosis and intervention of POPH, it is necessary to establish a simple screening method to identify patients with POPH [21]. A recent study reported a risk assessment for POPH using chest CT scans, which are frequently performed in patients with cirrhosis [11]. Moreover, CT is an accurate and established method to evaluate body composition, including muscle mass and fat mass, in patients with cirrhosis [16,17]. Body composition is known to be involved in the pathophysiology of patients with cirrhosis [16,17];

Association between Body Composition and Survival in Patients with Cirrhosis
The Cox proportional hazards regression model was used to evaluate the association between body composition and survival in patients with cirrhosis (Table S3). The analyses revealed that although SATI (HR, 0.98; 95% CI, 0.96-0.99; p = 0.004) was associated with survival in patients with cirrhosis, no such association was found for SMI and VATI.

Discussion
Since the mortality of candidates for LT with POPH is extremely high, there have been many studies on POPH among this population [7]. In addition, recent studies have attempted to explore POPH in patients with more preserved liver functional reserves [9,10]. For early diagnosis and intervention of POPH, it is necessary to establish a simple screening method to identify patients with POPH [21]. A recent study reported a risk assessment for POPH using chest CT scans, which are frequently performed in patients with cirrhosis [11]. Moreover, CT is an accurate and established method to evaluate body composition, including muscle mass and fat mass, in patients with cirrhosis [16,17]. Body composition is known to be involved in the pathophysiology of patients with cirrhosis [16,17]; however, studies on its relationship with POPH have been scarce. Therefore, we examined the association between body composition and the risk of POPH, defined by mPA-D dilatation and increased mPA-D/aAo-D [11], in cirrhotic patients using CT images.
The risk factors of POPH in patients with cirrhosis remain unclear. Previous studies have reported that female sex, etiology of cirrhosis, history of splenectomy, and portosystemic shunt may be associated with POPH [22][23][24], but it is uncertain whether liver functional reserves, the severity of liver fibrosis, and abnormalities in body composition are risk factors for POPH [9,10]. The results of the present study were the first evidence to show that cirrhotic patients with obesity had higher mPA-D and mPA-D/aAO-D, both of which are associated with the risk of POPH [11]. Detailed body composition analysis, adjusted for previously reported risk factors such as female sex, portosystemic shunt, and IVC dilation [2,11,24], also showed an increased risk of POPH in cirrhotic patients with increased SATI, VATI, and TATI. To the best of our knowledge, no report has focused on the association between POPH and obesity or increased adipose tissue. However, it has been reported in a large American hospitalized cohort that BMI strongly affects pulmonary vascular hemodynamics [12]. Studies have demonstrated that inflammation and endothelin-1 play an important role in the pathophysiology of POPH [25][26][27]. Since obesity is known to induce systemic inflammation and increase vascular endothelin-1 and endothelin-1 receptor expression [28], adipose tissue can function as a modulator of PH. This evidence supports our new findings that obesity and increased adipose tissue may be associated with the risk of POPH in patients with cirrhosis.
Another intriguing finding of the present study is that reduced skeletal muscle mass and obesity may be important classifiers for identifying patients at risk of POPH. Sarcopenia, characterized by reduced muscle mass and strength, has a significant role in the development of complications and outcomes in patients with cirrhosis [16]. However, to date, no studies have confirmed the association between sarcopenia and POPH. In meta-analyses, approximately 15.5% to 34% of patients with chronic obstructive pulmonary disease have sarcopenia, and these patients with sarcopenia have lower expiratory volume and poorer exercise tolerance [29]. Another study reported that lung transplant candidates with sarcopenia had an increased risk of delisting or mortality [30]. This evidence suggests that pulmonary disease's severity negatively impacts skeletal muscle. Furthermore, sarcopenia itself may strongly impair the prognosis of patients with pulmonary disease. In fact, patients with sarcopenia and without obesity showed worse survival than those without them in our study. Since POPH can lead to right heart failure [3], patients with POPH may easily develop sarcopenia resulting from exercise disability. Our findings provide the first evidence that reduced muscle mass may stratify the risk of POPH in patients with cirrhosis.
Other interesting findings in the present study are that female sex, portosystemic shunt, and IVC diameter were also associated with POPH risk using CT images. A prospective study has shown that the risk of POPH in females is approximately three times higher than that in males [22]. Similarly, our results showed that the probability of POPH high-risk in females is approximately two times higher than that in males. Another retrospective study has revealed that large portosystemic shunt is associated with the severity of POPH and response to treatment of POPH [24]. Furthermore, the study, which suggested the use of CT images for POPH screening, has also demonstrated that female sex, portosystemic shunt, and IVC diameter are independently associated with POPH risk in the multivariate logistic regression model [11]. Therefore, the results of the present study not only provided new evidence in body composition and POPH risk but also strengthened the evidence of previously reported pathophysiology of POPH.
As for the association between body composition and survival, we additionally found that SATI was associated with survival in patients with cirrhosis. This is supported by a recent study that revealed that there is a U-shaped association between SATI and mortality in patients with cirrhosis [31]. Furthermore, this study also revealed the prognostic significance of sarcopenic obesity in patients with cirrhosis. Given their robust impact on survival, assessing body composition, sarcopenia, and obesity is a fundamental step in stratifying the risk of adverse outcomes in patients with cirrhosis.
The limitations of our study are as follows. Firstly, this single-center retrospective study may include bias and confounding factors. Secondly, since we did not perform the right heart catheterization in this study, the association between body composition and pulmonary vascular hemodynamics was unsatisfactory in patients with cirrhosis. A previous study has suggested the usefulness of chest CT findings for assessing POPH risk [11]. However, the assessment of POPH risk using CT findings should be considered with caution because we found that chest CT findings of PH are affected by body composition. Furthermore, since the latest guideline recommends the use of echocardiography for the screening of POPH [32], the usefulness of echocardiography for screening POPH and its association with body composition should be evaluated in future studies. Third, body composition has variations, and our findings may not be adapted to other ethnicities and legions. Therefore, further multicenter studies with right heart catheterization are required to validate the relationship between body composition and POPH in patients with cirrhosis.

Conclusions
In conclusion, obesity and reduced skeletal muscle mass may strongly affect the expansion of mPA-D assessed using chest CT. Abnormal body composition is closely associated with prognosis and complications in patients with cirrhosis. Therefore, assessment of body composition is extremely important in diagnosing cirrhosis complications and in practicing prevention and treatment to improve the prognosis of cirrhosis patients. Since the present study lacked data on right heart catheterization, further studies are required to confirm the results of our study.
Supplementary Materials: The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/jcm12103351/s1, Table S1: Univariate analysis predicting POPH high-risk in patients with cirrhosis; Table S2: Multivariate analysis for predicting POPH high-risk in patients with cirrhosis; Table S3: Impact of body composition on survival in patients with cirrhosis; Figure S1: Association between sarcopenia, obesity, and survival in patients with cirrhosis. Informed Consent Statement: An opt-out method was used to obtain informed consent from all the patients due to the retrospective nature of this study.

Data Availability Statement:
The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.